Method of treating inflammation

Agent: Regimbeau, Corre and Paillet.

(30) Conventional priority: Patent application filed in the United States of America on December 1, 1967, n. 687.101 on behalf of Bruce Edward Witzel, Conrad Peter Dorn and Tsung-Ying Shen.

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the present invention relates to the application of a family of compounds to the treatment of inflammation. In this family, some of the compounds are new and are therefore considered as new drugs having in particular anti-inflammatory properties.

the treatment of inflammation according to the invention comprehended the oral administration to a patient of 0.5 to 30 mg per kg of body weight per day of a compound corresponding to one of the two formulas I and following II

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I II in which:

is hydrogen, or a lower alkyl group, phenyl, lower aralkoyl, halo, lower halo-alkyl, lower alkoxy, amino, dialcoyl. lower-amino, dialcoyl. lower-amino-lower alkyl, nitro, lower alkyl-sulfonyl, phenylsulfonyl, phenoxy, sulfo or triphenylmethyl;

© if hydrogen or a lower alkyl, lower alkenyl, hydroxy, amino, lower alkynyl, phenyl, substituted phenyl, lower aralkoyl, lower aralkenyl, benzamido, aleanoyl. lower-amino, carbobenzoxyamino, caralcoxy.lower-amino, benzylidinamino, phenylureido, amino-lower alkyl, lower alkyl-lower amino-lower, dialkoylower-lower amino-aleoyl, lower alkanoyl, lower aleoyl, hydroxy carboxyalkyl -lower aloyl, or lower cyanoalkyl;

R ^ is hydrogen or a lower aleoyl radical;

R ^ and R ^, which are identical or different, are hydrogen or lower alkyl, phenyl, halo, trihalo-lower alkyl, lower alkoxy, amino, lower-amino-dialkyl, nitro, cyano, sulfamoyl, alkyl. lower sulfamoyl, lower dialkoyl-tallowamoyl, hydroxy, mercapto, lower alkyl-thio, lower alkyl-tallow, lower alkyl tallow onyl, carbamoyl, carboxy, sulfo or phenylsulfonyl;

Rg is oxygen or sulfur;

R? represents ORg or SRg, where s

Rg is a lower alkanoyl, lower alkyl, benzyl, nitrobenzyl, lower alkyl-benzyl, halobenzyl, amino benzyl, lower alkyl-amino-benzyl, lower alkoxy-benzyl, methylenedioxybenzyl; and is an earboeyelic or heterocyclic aryl group such as phenyl, thiazolyl, thienyl, pyridyl or furyl, and is linked at position 3 or 4.

In the past, a classic method of treating inflammation was to administer various compounds from the steroid class. These compounds had the serious disadvantage of affecting calcium in the bones after prolonged administration. Recently, non-steroid drugs have been proposed which largely eliminate this defect. However, there remains the problem of certain other side effects such as hematological phenomena and irritations in the gastrointestinal tract. It is therefore necessary to find new compounds for the treatment of inflammation which further reduce the side effects observed during chronic administration.

The Applicant has determined that inflammation can be treated advantageously with the family of compounds generically known as 3- or 4-phenyl-2 - / * 1H_7- pyridones including the base compound from each of the series, namely 3- or 4-phenyl2- / ~ 1H7 ~ pyridone. The treatment of inflammation with this family of compounds has fewer side effects than with the previous remedies, while having excellent efficacy.

The compounds which can be used according to the invention have one of the structures I or II above, with the various substituents having the definitions already given. The new compounds which can be used in this method are those which are defined as ei-des3us with the additional conditions that when R₁is a phenyl group, R ^ is a lower alkyl radical; when R₁ is a lower alkyl radical, R ^ is hydrogen and when Rg is one. lower alkyl radical, Rj is other than hydrogen.

The preparation of the compounds of the invention is described in the diagram below for the compounds of 3-phenyl-2- / ~ 1 H_7 ~ pyridone. The reactions described are also suitable for 4-phenyl compounds. Generally, a 3- or 4-aminopyridine is diazotized in the presence of benzene or a substituted benzene. The 3-phenylpyridine obtained is then oxidized to give the corresponding H-oxide. The H-oxide can be transformed into 3-phenyl-2- / ~ 1 H ^ -pyridone by two methods. In the first, the H-oxide is heated with a lower alkanoic anhydride oe which, by transposition, gives 2-aeyloxy

3- or 4-phenylpyridine which, by acidic or preferably basic hydrolysis, gives 3- or 4-phenyl-2- ^ ~ 1H_7-pyridone. In the second process, the H-oxide is treated with a chlorination agent which again, by transposition, leads to the corresponding 2-ehloropyridine which, by hydrolysis, gives 3- or 4-phenyl-2- / ~ 1 H_7pyridone . 2-ohloro-3-phenylpyridine oxide is also prepared by direct oxidation of 2-chloro-3-phenylpyridine. 3- or 45 phenyl-2- /^-1HjZ-pyridones (Compound VI in the scheme) can be transformed into 3- or 4-phenylthiopyridones by treatment with phosphorus pentasulfide. 3- or 4-phenyl-2- / ~ 1H_7-pyridon.es of compound VT can be transformed into 3- or 4-phenyl-2 / ”lE_7-pyridones substituted into 1 of compound IX by the action of alkylating agents. Certain other compounds which can be used according to the invention, namely the 3-phenylalkoxy or alkylthiopyridines (Compound XI) are prepared from the 2-chloropyridines using a sodium alcoholate or thioaleoolate. When 3- or 3-

4- (nitrophenyl) -pyridones, the nitro group can be reduced to an amino group and the latter can be used, by a Sandmeyer reaction, to prepare halo, cyano, mercapto derivatives, etc.

the diagram also shows another process for preparing

3- or 4-phenyl-2- /^—1H_7-pyridones which is the oxidation of 3- or

4- corresponding phenylpiperidones. It should be noted that the reactions indicated in the diagram are numbered with numbers corresponding to; Examples which follow in this memo and which illustrate these reactions.

the other methods have been described in the literature for the preparation of 3- or 4-phenyl-2- / ï H_7-pyridon.es. A 3- or 425 amino 2-halopyridine can be diazotized in the presence of a benzene to give Compound VII directly, nitrobenzenes can be heated with pyridines at very high temperatures to produce 3- or 4-phenylpyridines. An open chain substituent on a benzene compound can be cyclized to form the pyri30 done ring or a piperidone ring which can be oxidized as described above to give 3- or 4-phenyl-2- / 1H-7-pyridone. Uh 3- or 4phenylpyridine-2-sulfonic acid, by fusion with a caustic, gives a

3- or 4-phenyl-2 - / “1H_7-pyridone. An œ-pyrone can be treated with ammonia to give a 3- or 4-phenyl-2-7lH_7-pyridone. Of

3- or 4-phenylpyridines can be hydroxylated directly in the vapor phase. 3- or 4-phenyl-2-aminopyridines can be diazotized and the diazo compound hydrolyzed to give a 3- or 4-phenyl-2- / ~ 1 H_7pyridone. the H-oxides (Compound IV) can be transposed under the influence of light to give 3-phenyl-2 - / “lH_7-pyridones · 3- or 4-phenyl-2- / ~ 1H_7 ~ pyridones substituted in 1 (Compound IX) can be prepared by direct oxidation of the compounds of 3- or

4- corresponding phenyl-N-pyridinium. These various preparations in general are not as practical for the synthesis of these compounds as those which are described in the diagram, because either they are specific of the compounds to be used, or they give less good yields or have other disadvantages .

In the treatment of inflammation with the products of the invention, the medicament can be administered orally or intravenously or be applied topically. It can be used with any common pharmaceutical excipient. In the formulations it can be presented in the form of tablets or tablets or be encapsulated or dissolved in isotonic solutions for intravenous use or produced in ointments for topical use. The conventional pharmaceutical ingredients normally employed in pharmaceutical formulations can be used to formulate these products. Inflammation is treated by administering 0.5 to 30 mg of the compound per kg per day. An example from the above family is the simple unsubstituted 3-phenyl-2 - ^ “1H_7 ~ pyridone which should be administered in a dosage ranging from 2 to 15 mg per kg per day. 3-phenyl-2-2 ~ 1Hj7-pyridone is effective at a dose of 10 - 30 mg per kg in rats.

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J.

DIAGRAM

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IX

Reactions

1. Addition of amyl nitrite or to amyl nitrite with or without inert solvent, then heating, the amyl nitrite can be replaced by other organic nitrosating agents soluble in organic solvents.

2. Oxidation in an inert solvent. HgOg is the preferred agent.

2a. Oxidation in an inert solvent (eg acetic acid) with peracetic acid.

3. (a) Heating with a lower alkanoic anhydride in an inert atmosphere. Acetic anhydride is preferred.

(h) Hydrolysis, in general by contact with water, also in the presence of alkali or acid.

4. (a) Heating with a chlorinating agent, such as PCl ^ in an inert solvent.

(h) Hydrolysis, generally by concentrated hase.

5. Heating with a dehydrogenating agent such as palladium on black in an inert atmosphere.

6. Reaction with a strong base, for example NaH in an inert atmosphere, then addition of an alkylating agent such as an aliphatic tosylate, a sulphate or an aliphatic halide.

7. Heating with a strong base (for example NaOH) and an unsaturated organic compound like acrylonitrile or an o-halogenacid derivative like chloracetic acid. (The latter process is described in J. Am. Chem. Soc. 71, 1949, p. 390). 1-carboxy methyl-3-phenyl-2-pyridone, melting at 93-96 ° C can be prepared by this method.

J "

8423₇

8. Reaction with a strong base such as NaH in an inert atmosphere, then heating with iodobenzene or a substituted iodobenzene.

9 · Stirring at low temperatures, preferably cold, with an N-halo-amino compound.

W. Heating with an alkanoic acid anhydride, preferably with acetic anhydride at 130-140 ° C.

11. Heating with (ⁱⁿ the absence of 0Ξ group, ketone or amino in the molecule).

12. Heating with a metallic alkoxide or another alcoholate.

13. Heating with a metallic mercaptide.

The invention can be illustrated by the following examples. Example 1 A. The 3-aminopyridine (39 g) in 1.5 l of anhydrous benzene is treated with amyl nitrite (68 g) and the resulting mixture is heated slowly to 81 ° C. and maintained for at night at - this temperature. The solution is decanted to separate a little tar which has precipitated and the excess benzene is removed under vacuum.

Distillation of the residue provides 3-phenylpyridine (38 g; 590), in the form of a yellow oil boiling at 102-105.5 ° C (2.5 mm).

The same, by replacing 3-aminopyridine with 4-aminopyridine, 4-phéhylpyridine is obtained.

B. Similarly, when the benzene, in part A above, is replaced by the following products: toluene, anisole, benzonitrile, nitrobenzene, fluorobenzene, benzotrifLuorare, ηε £ ύalene, o-, m- and p-xylene, o- , m- and p-dichlorobenzene, hydroquinone dimethyl ether, veratrole, resorcinol dimethyl ether, biphenyl, thiophene, furan or thiazole, the corresponding substituted phenylpyridines are obtained, namely: 3- (o-, m- and p-methylphenyl) pyridines, 3- (o-, m- and p-methoxyphenyl) -pyridines, 3- (o-, m- and p-cyanophenyl) pyridines, 3- (o-, m- and p-nitrophenyl) pyrid ± nes, the 3- (o-, m- and p-fluoroph'ényl) pyridines, the 3- (o-, m- and p-trifluoromethylphenyl) - pyridines, 3- (œ and £ -naphthyl) -pyridines, 3- (o, m-, m, p-, o, o * -, o, p-, m, m'and o, "'- dimethylphenyl) -pyridines, the 3- (o, m-, m, p-, o, o'-, m, m * -, and o, m'-dichloroph.enyl) -pyridines, the 3- (o, m-, m, p-, £, o'-, o, £ -, m, m'35 and o, m'-dimethoxyphenyl) -pyridines, 3- (o-, m- and p-biphenylyl) pyridines, 3- (2-thienyl) -pyridines, 3- (2 'and 3'-furyl) pyridines and 3- (2'-, 4'- and 5'-thiazolyl) pyridines, the isomers being separated by fractional distillation and / or by column and vapor phase chromatography.

C. 3-Aminopyridine (39 g) in 1.5 liters of anhydrous chlorobenzene is treated with amyl nitrite (68 g) as described in A above. By distillation of the concentrated reaction mixture, 35.4 g of the three isomers boiling at 110-130 are obtained^ûC under ί 8423

2.5 mm approximately. The fraction boiling at 110-113 ° C under about 2.5 mm consists of 11.5 g of almost a single component. The infrared, ultra-violet spectra, nuclear magnetic resonance and thin layer chromatography on this product and products derived therefrom show that it is the ortho isomer. The other isomers are isolated from the fractions with higher boiling point by purification of their picrates, then regeneration of the free bases. When 4-aminopyridine is used in place of 3-aminopyridine in the above procedure, the corresponding 4-phenylpyridines are obtained.

D. In cases where the body used in place of benzene is a solid, an inert co-solvent is used and the quantity of this body replacing benzene is reduced. The phenylpyridines listed in A above can also be obtained by coupling a substituted aniline such as o-ehloroaniline, with pyridine by the above method and by separating the is-, β- and μ-pyridines to obtain the 3- (substituted phenyl) -pyridines desired.

B. When, instead of 3-aminopyridine,

5-amino-2-picoline with the same procedure A above, we

Obtains 6-methyl-3-phenyl-pyridine. D_e analogously, if, with the same procedure, 3-aminopyridine is replaced by the following products: 5-amino-3-picoline, 3-amino-4-picoline, 5-amino-2ehloropyridine, 3-amino-5- chloropyridine, 3-amino-4-chloropyridine,

5-amino-2-methoxypyridine, 3-amino-5-methoxypyridine, 3-amino-425 methoxypyridine, 5-amino-2-nitropyridine, 3-amino-5-nitr © pyridine,

3- amino-4-nitropyridine, 5-amino-2-ethoxypyridine, 3-amino-5-ethoxypyridine, 3-amino-4-ethoxypyridine, 5-amino-2-ethylpyridine, 3-amino4- ethylpyridine, 5-amino- 2-phenethylpyridine, 3-amino-4-phenethylpyridine, 5-amino-2-fluoropyridine, 5-amino-2- (methylsulfonyl) pyridine, 3-amino-4- (methylsulfonyl) -pyridine, 5-amino-2- (phenylsulfonyl) -pyridine, 5-amino-3-chloro-2-phenoxy-pyridine, 5-amino-2methoxy-4-picoline, and 5-amino-5-phenyl-4-picoline, the following products are obtained: 5- »ethyl-3-phenylpyridine, 4-methyl-3-phenylpyridine, 6-chloro-3-phenylpyridine, 5-chloro-3-phenylpyridine, 435 chloro-3-phenylpyridine, 6-methoxy-3-phenylpyridine, 5- methoxy-3phenylpyridine, 4-methoxy-3-phenylpyridine, 6-nitro-3-phenylpyridine,

5- nitro-3-phenylpyridine, 4-nitro-3-phenylpyridine, 6-ethoxy-3phenylpyridine, 5-ethoxy-3-phenylpyridine, 4-ethoxy-3-phenylpyridine,

6- ethyl-3-phenylpyridine, 4-ethyl-3-phenylpyridine, 6-phenethyl-340 phenylpyridine, 4-phenethyl-3-phenylpyridine, 6-fluoro-3-phenylpyridine, 6-methylsulfonyl-3-phenylpyridine, 4-methylsulfonyl -3-phenylpyridine, 6-phenylsulfonyl-3-phenylpyridine, 5-chloro-6-phenoxy-3-phenylpyridine, S-aethoxy-4-methyl1-3-phenylpyridine and 3,5-diphenyl-4ï 8423 methylpyridine.

E. When the substituted benzenes of B are used instead of the benzene used in E above; the pyridines containing a corresponding substituted phenyl substituent are obtained.

G. 3-amino-2-ehloropyridine (5.1 g) in 50 ml of anhydrous benzene is added dropwise to 150 ml of benzene in 32 minutes, to which 8 ml of isoamyl nitrite has just been added and which is maintained at 5O-56 ° C. The mixture is heated at 75 ° 0 for 2 hours and treated as in A^-to give 2-chloro-3-phenylpyridine.

H. Likewise, when the benzene in the above reaction is replaced by pyridine, methylphenylsulfide or any of the benzene substitutes used in B, the corresponding 2-chloro-3arylpyridines are obtained. Products are mixtures of the isomeric arylpyridines and the isomers are separated by fractional distillation and / or by column and vapor phase chromatography. In this way, the following products are obtained: 2-ehloro-3-2 *, 3'and 4'-pyridino) -pyridines, 2-chloro-3- (o-, m- and p-methylthiophenyl) pyridines, 2-chloro-3- (o-, m - and jMnethylphenyl) -pyridines, 2-chloro3- (o-, m- and p-methoxyphenyl) -pyridines, 2-chloro-3- (o-, m- and p-cyanophenyl) -pyridines, 2-ehloro-3 - (o-, m- and p-nitrophenyl) -pyridines, 2-chloro-3- (o.-, m- and p-fluorophenyl) -pyridines, 2-chloro-3- (o-, inet p-trifluoromethylphenyl ) -pyridines, 2-chloro-3- (œ and β-naphtyi) pyridines, 2-chloro-3- (o, m-, m, £ -, o, o'-, o, p-, m, m * - and o, m'-dimethylphenyl) -pyridines, 2-chloro-3- (o, m-, m, £ -, 2 »£ ~» 2, p-, m, m- and o, »'Dichlorophenyl) -pyridines, 2-chloro-3- (o, m-, m, p-, £, o · -, o, p-, m, m'et o, m'-dimethoxyphenyl) -pyridines, 2-chloro-3- (o-, m and p-biphenylyl) pyridines, 2-chloro-3- (2-thienyl) -pyridines, 2-chloro-3- (2- and 3furyl) -pyridines and 2-chloro -3- (2 * -, 4'- and 5'-thiazolyl) -pyridines. Example 2 A. 3-o-chlorophenylpyridine (11.4 g) in 40 ml of glacial acetic acid is treated at 27 ° C with 7 ml of a 30% hydrogen peroxide solution. the mixture is moderately heated, in this case 75-2 ° C is preferred, a temperature which is maintained overnight; during this period, another 6 ml are added, then 3 ml of hydrogen peroxide. After cooling, solid sodium bisulfite is added in an amount desired to destroy the excess peroxide, the mixture is concentrated to approximately half its volume, 75 ml of water are added, the mixture is concentrated approximately to a third of its initial volume, 100 ml of water are added and evaporated to dryness. Remaining oil is dissolved in 150 ml of chloroform, solid anhydrous sodium carbonate is added to basic pH, the mixture is filtered, the volume of the chloroform solution is reduced to approximately 45 ml and water is slowly added. petroleum ether with stirring to a volume of approximately 250 ml. White solid which precipitates is separated by filtration, washed with petroleum ether and dried. 8.4 g of 3-o-chlorophenylpyridine-nooxide are obtained, melting at 118-123 ° C, IR 8.26 | i, This product is used without further purification in 3B.

B. Similarly, when the 3-o-chlorophenylpyridine in the above reaction is replaced by the other 3- or 4-phenykpyridines in Example 1, the corresponding N-oxides are obtained.

C. Similarly, when, in the procedure of Example 1, the following products are used: 4-phenylpyridine, 4- (p-tolyl) pyridine, 4- (isopropylphenyl) pyridine, 4- (hiphenylyl) -pyridine , 4 - (] £ chlorophenyl) -pyridine, 4- (p-bromophenyl) -pyridine, 4- (o-methoxyphenyl) -pyridine, 4- (m-methoxyphenyl) -pyridine, 4- (jt-methoxyphenyl) pyridine, 4 - (^ - ethoxyphenyl) -pyridine, 4- (o, m- or p-nitrophenyl) pyridine, the corresponding N-oxides are obtained.

Example 3 »

AT. 3-phenylpyridine-N-oxide (9.2 g) and 25 ml of acetic anhydride are heated in an oil bath at 153 ° C (bath temperature), under a nitrogen atmosphere, the stirred mixture is kept 11 hours at this temperature, then allowed to cool to room temperature, and the dark mixture is added slowly to a stirred mixture of ice and water (250 ml) covered with about 50 ml of ether, the oily mixture solidifies , the solid is filtered, washed thoroughly with water and ether and dried to give 7.7 g of an almost pure brown solid. By recrystallization from dimethyl sulfoxide, then from chloroform (darco), white eristals are obtained, melting at 225-227 ° 0, of 3-phenyl-2- / ~ 1hJ7 -pyridone.

B. 3- (o-ohlorophenyl) -pyridine-N-oxide (4.1 g) and acetic anhydride (10 ml) are heated, under nitrogen, in an oil bath at 146-2 ° C ( bath temperature) and kept at this temperature for about 11 hours. After cooling, the mixture is added to a stirred mixture of ice and water (80 ml) and the resulting oil is taken up in chloroform, the chloroform is removed in vacuo, the residue is dissolved in 60 ml of methanol, 7 ml of water and 2 ml of saturated sodium bicarbonate solution; the mixture is refluxed for approximately 15 minutes, the mixture is made neutral with 2.5 N hydrochloric acid, the solvents are removed and the mixture is treated with chloroform and water, the chloroform layer is dried, freed from the solvent and the residue is recrystallized from benzene to give 635 mg of white 3- (o-chlorophenyl) -2- / ~ 1H_7-pyridone melting at 203.5-207 ° C.

C. Alternatively, acetic anhydride can be removed directly under vacuum by immediately following methanol-bicarbonate treatment.

D. When the substituted pyridine oxides of Example 2 are used in. instead of 3- (o-chlorophenyl) pyridine oxide in the above reaction, the 2- ^^-1H_T'-pyridones corresponding.

3- (o-, m- and p-methylphenyl) -2- / ~ 1H_7-pyridines,

3- (m- and p-chlorophenyl) -2-2 ”1Hy-pyridones,

3- (o-, m- and p-methoxyphenyl) -2-2 ”1Hy-pyridones,

3- (o-, m- and p-cyanophenyl) -2- /^-1H_7'-pyridones,

3 - (&lt;3—, m- and p-nitrophenyl) -2- ^^-1HjT-pyridones,

3- (o-, m- and p-fluorophenyl) -2-2 ~ 1Hy-pyridones,

3- (o-, m- and p-trifluoromethylphenyl) -2-_&lt;/ ~ 1H_7-pyridûnes,

3-œ- and £ -naphthyl-2-2^_1Hy-pyridones,

3- (o, m-dimethylphenyl) -2-2 ”1 Hy-pyridone,

3- (m, p-dimé thylphenyl) -2-2 ”1 Rjf-pyridone,

3- (o, o¹ -dimed thylphenyl) -2 ~ 2 ”1 Hy-pyridone,

3- (ο, p-dimé thylphenyl) -2 ~ 2 ”1Hy-pyridone,

3- (m, m * -dimethylphenyl) -2 ~ 2 ”1 Hy ~ pyridone, 3- (o, m'-dimethylphenyl) -2-2” 1 Hy-pyridone, the corresponding dichloro and dimethoxy phenyl pyridones,

3- (o-, m- and p-biphenylyl) -2-2 ”lH_7-pyri (ions,

3- (2 · -thienyl) -2-2 ”1Hy-pyridone,

3- (2'-furyl) -2-2 ”1 Hy-pyridone,

3- (3 '-fnryl) -2 ~ 2 ”1 Hy-pyridone,

3- (2'-thiazolyl) -2 ~ 2 ”1H_7-pyridone,

3- (4 '-thiazolyl) -2-2 ”1 Hy-pyridone,

3- ζ 5¹ -thiazolyl) -2-2 ”1 Hy-pyridone,

6-methyl-3-phenyl-2-2 ”l Hy-pyridone,

5- me thyl-3-phenyl-2 ~ 2 ~ 1 Hy ~ pyr idone,

4- methyl-3-phenyl-2 ~ 2 ”1 Hy ~ pyridone,

6,5- and 4-chloro-3-phenyl-2-2 ~ 1Hy-pyridones,

6,5- and 4-methoxy-3-phenyl-2-2 ”1Hy-pyridones,

6,5- and 4-nitro-3-phenyl-2-2 ”1Hy-pyridones,

6,5- and 4-ethoxy-3-phenyl-2-2 ~ 1Hy-pyridones,

6- and 4-ethyl-3-phenyl-2-2 ”1Hy-pyridones,

6- and 4-phenethyl-3-phenyl-2-2 ”1Hy-pyridones,

6-fluor o-3-phenyl-2-2 ”1 Hy-pyridone,

6- and 4-methylsulfonyl-3-phenyl-2-yiHy-pyridones,

6-phenylsulf onyl-3-phenyl-2-2 ”1 Hy-pyridone,

5- chloro-6-phenoxy-3-phenyl-2-2 ”1 Hy-pyridone,

6-methoxy-4-methyl-3-phenyl-2-2 Ӕ Hy ~ pyridone,

4-methyl-3, 5-diphenyl-2-2 ”1 Hy-pyridone, and the phenyl derivatives substituted in 3 corresponding to the above compounds.

E. In the above cases, the induction effects of the killings on the phenyl and pyridine cycles help to determine the course of transposition, and in some cases the

5- phenyl-2- / ~ 1H_7-pyridones. The isomers are separated by recrystallization techniques and column chromatography ·

Example 4 A. 2-methyl-5-phenylpyridine-N-oxide (1 g), phosphorus pentachloride (1.2 g) and dry chloroform (10 al) are heated at reflux in a water bath for one hour . Ice is added to the cooled solution which is then basified with potassium carbonate. The chloroform layer is separated, dried over calcium chloride and concentrated to give crude 2-chloro-3-phenyl6-methylpyridine.

B. The basic hydrolysis of this compound gives 6-methyl-3phenyl-2 - / “1ïï_7-pyridone.

Example 5 3-Phenyl-3,4,5,6-tetrahydra-2-pyridone (1 g) and Pd / C at 30% (0.5 g) are intimately mixed, placed under a nitrogen atmosphere and heated in a metal bath set to 270 ° C. the mixture is left for 8 hours, cooled; the residue is extracted several times with boiling chloroform, the solvent is removed and the residue is chromatographed on a column of silica gel using an acetone-ether system (v / v 0-50%) as eluent, which gives 3-phenyl-2- / ~ 1H_7-pyridone.

Example 6 - 1-methyl-5-phenyl-2- / ~ 1H_7-pyridone.

A. To a stirred suspension of 0.87 g of 50% NaH (0.018 M) is added at 5 ° C under nitrogen 3.08 g (0.018 M) of 3-phenyl-2 - / “1H_7pyridone. The mixture is stirred for half an hour at ambient temperature, cooled to 5 ° C. and 2.84 g (0.020 M) of methyl iodide are added. The reaction mixture is stirred for 3 hours at room temperature, then it is concentrated in vacuo. The residue is extracted between methylene chloride and water containing a little hydrochloric acid. The combined chloroform extracts are dried over sodium sulfate and concentrated. The residue is recrystallized from methylene chloride and hexane to give 1.9 g of 1-methyl-335 phenyl-2 - / “1H_7-Pyridone melting at 135-137 ° C.

B. Likewise, when other alkyl halides are used, such as ethyl bromide, butyl bromide, propyl bromide, etc., instead of the methyl iodide of the example above. above, the corresponding 1-alkyl-3-phenyl-2 - / ”1H 7-pyridones are obtained.

Likewise, when allyl bromide, methallyl chloride and crotyl chloride are used instead of methyl iodide in the example above, the 1-allyl-, 1-methallyl- and

1-crotyl-3-phenyl-2- ^ “1 H_7-pyridones.

y.

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D. When henzyl chloride, â * &amp;, m- or pchlorobenzyl, o-, m- or p-methylbenzene, o-, m- or p-fluorobenzyl, o-, m- or p-methoxybenzyl, 3,4-dichlorobenzene, 3,4dimethoxybenzyl or pentafluorobenzyl bromide, instead of methyl iodide, 1-arylmethyl-3-phenyl-2-7 are obtained^_1H_7pyridones.

E. When oinnamyl bromide is used instead of methyl iodide, 1-cinnamyl-3-phenyl-2- is obtained /^-1H_7pyridone.

E · When using propargyl bromide instead of methyl iodide, we obtain 1-prapargyl-3-phenyl-2- /^-1H_7-pyridone.

&amp;. When methyl iodide is replaced in the above process by 2-chloroethylamine, H-methyl-2-chloroethylamine, H, N-dimethyl-2-chloroethylamine, H-ethyl-2-chloroethylamine, H, H-diethyl-2-chloroethylamine, H- (2-chloroethyl) -piperidine or 3-chloropropylamine, the corresponding 3-phenyl-2- / ~ 1 H_7-pyridone is obtained.

H. When methyl iodide is replaced by chloracetone, 1-chloro-propan-2-one and phenacyl chloride, the corresponding 1-acylmethyl-3-phenyl-2- / 1H_7-pyridone is obtained .

I. When the methyl iodide is replaced by 2-bromoethanol or 2-bromopropanol in the above procedure, the corresponding 1-hydroxyalkyl-pyridone is obtained.

EXAMPLE 7 A mixture of 0.02 mole of 3-phenyl-2- / ~ 1/7-pyridone and

0.02 mole of acrylonitrile is heated with 0.1 g of solid sodium hydroxide in a steam bath until the reaction takes place. When the exothermic reaction stops, the reaction mixture is heated in a steam bath for one hour, then cooled. The residue

3D is taken up in chloroform and is washed with water; the chloroform extract is dried over sodium sulfate and concentrated. Chromatography of the residue on 400 g of silica gel and elution with an ether-petroleum ether mixture (0-70%) gives 1- (2-eyano-ethyl) 3-phenyl-2- / ~ 1H_7- pyridone.

Example 8 A. Sodium 3-phenyl-pyridone To a suspension of 0.87 g of 50% HaH (0.018 m) in 100 ml of dry benzene, 3.08 g (0.018 m.) Of 3-phenyl- is added. 2- / ~ 1H_7 pyridone. The reaction mixture is heated at 35 ° C for 6 hours and stirred at room temperature overnight. The benzene is then evaporated under vacuum, which leaves a residue of sodium 3-phenylpyridone.

B. 1.3-diphenyl-2- / ~ 1H 7-pyridone The 3-phenyl-pyridone sodium previously obtained (0.018 m.),

6.04 g of iodobenzene (0.032 m.) And 0.19 g of copper (0.003 m.) Are mechanically mixed and heated at 155 ° C under nitrogen for 6 hours. The reaction mixture is allowed to cool overnight to temperature ambient and the mixture is extracted thoroughly with chloroform.

The chloroform extracts are washed with water, dried over sodium sulfate and concentrated. Chromatography of the residue on 500 g of silica gel and elution with an ether-petroleum ether mixture (0-75 0) give 1,3-diphenyl-2- / ~ 1H_7-pyridone.

0. The same, when iodobenzene is replaced by substituted iodo10 benzenes, for example 2-, 3- or 4-iodonitrobenzene, we obtain the 3-phenyl-2- / ~ 1H_7-pyridones comprising in 1 a corresponding substituted aryl.

Example 9 - 3-phenyl-1- (2 '-quinolyl) -2 - / * 1Hj7-pyrldone A. 2-bromo-5-phenyl-pyridine A mixture of 0.1 mole of 3-phenyl-2- / ”LH_7-pyridone and

0.15 mole of phosphorus tribromide is heated at 180 ° 0 for 3 hours. The reaction mixture is cooled, decomposed in ice water, basified with sodium hydroxide and extracted thoroughly with ether. The combined ethereal extracts are dried over sodium sulfate and concentrated in vacuo to give 2-bromo-3-phenylpyridine ·

B. 5-phenyl-1 - (2 '-quinolyl) -2 - / * 1 H_7-pyridone A mixture of 0.02 mole of quinoline-N-oxide and 0.022 mole of 2-bromo-3-phenyl-pyridine is heated in a steam bath for

8 hours. The reaction mixture is cooled, taken up in water containing a little hydrochloric acid and washed with ether. The aqueous layer is made alkaline with potassium carbonate and thoroughly extracted with chloroform. The combined chloroform extracts are dried over potassium carbonate and concentrated to give the

3-phenyl-1- (2'-quinolyl) -2- /^- 1H_7-pyridone.

C. Similarly, if we replace the quinoline-N-oxide used above with 2-, 3- or 4-pieoline-N-oxide, we obtain 3-phenyl-1 / ~ 2 '- (6'-, 5 "- or 4 '-) methylpyridyl_7-2 - /" 1H_7-pyridone.

Example 10 A solution of chloramine is prepared by treating at 0 ° C ml of a neutral aqueous solution of sodium hypochlorite 1.93 m. (0.125 m.) With 20 ml of NH ^ OH 1.84 m. (0.375 m.). The above mixture is placed for one hour in an ice-salt bath, then 0.125 m is added. of sodium 3-phenyl-pyridone. The reaction mixture is stirred overnight at 0-10 ° C and is continuously extracted with ether for 24 hours. The ethereal extracts are dried over sodium sulfate and concentrated to give 1-amino3-phenyl-2- /^- 1H_7-pyriclone.

Example 11 - 1-hydroxy-3-phenyl-2- / ~ 1 Hj7 - pyridone A. 2-ehloro-3 ~ phenyl-pyridine-N-oxide 0,2 mole of 2-chloro-3-phenyl-pyridine- N-oxide are treated with 25 ml of glacial acetic acid and 22 ml of 40% peracetic acid. the temperature of the reaction mixture is maintained at 70 ° 0 for 3 hours, the reaction mixture is concentrated, extracted with chloroform and the chloroform extracts are concentrated to

J * give 2-chloro-3-phenyl-pyridine-N-oxide.

B. 0.01 mole of the latter product and 20 ml of acetic anhydride are heated for 3 hours at 13O-14O ° C. The reaction mixture is then concentrated under vacuum to give the crude 1-hydroxy-3_phenyl-2 / ~ 1H_7-pyridone.

Example 12 A. A mixture of 0.02 mole of 3-phenyl-2 - / ”1H_7-pyridone and

0.025 mole of phosphorus pentasulfide is heated at 160 ° C for hours. The reaction mixture is then poured into 100 ml of hot water, then is cooled and 3-phenyl-2 / ”1H_7-thiopyridone is obtained by filtration. By chromatography on 400 g of silica gel and elution with an ether-petroleum ether mixture (0-90 μl), the pure product is obtained, melting at 229-237 ° C.

B. Similarly, if we replace in example ei above 3-phenyl2- / ~ 1H_7-pyridone with other substituted pyridones, we obtain the 2- [~ 1 H_7-thiopyridones corresponding ·

Example 13 A. 2-methoxy-3-phenyl-uyridine A mixture of 0.01 mole of 2-chloro-3-phenylpyridine,

0.01 mole of sodium methoxide and 50 ml of dry dimethylformamide is heated at 60 ° C for 2 hours. The reaction mixture is concentrated in vacuo, taken up in chloroform and washed with water. The chloroform extract is dried over sodium sulfate and concentrated, the residue is chromatographed on 250 g of silica gel. By elution with an ether-petroleum ether mixture (0-75 μl), 2-methoxy-3-phenyl-pyridine is obtained.

B. Likewise, when substituted 2-chloro-5-phenyl-pyridines are used instead of 2-chloro-3-phenyl-pyridine, the corresponding 2-methoxy-phenyl-pyridines are obtained. When using other alkoxides such as sodium ethoxide or propoxide, sodium phenolate, sodium o- or p-chlorophenolate or p-methoxyphenolate, alloxide, crotoxide or sodium methalloxide , sodium propargoxide, benzoxide, chlorbenzoxide or sodium methoxybenzoxide, sodium cinnamoxide, 2-aminoethoxide, 2-aminopropoxide, 2-dimethylaminoethoxide, 3-dimethylaminopropoxide or sodium methylaminoethoxide or methoxyethoxide or sodium ethoxypropoxide, the corresponding alkoxyphenylpyridines are obtained. The alkoxides are prepared by adding 0.01 mole of alcohol in 20 ml of dry dimethylformamide to 0.01 mole of Eai in 30 ml of dry dimethylformamide and stirring for

1 hour.

EXAMPLE 14 The procedure of Example 13 is repeated except that the sodium salt of methyl mercaptan is used instead of sodium methoxide. The corresponding 2-methyl-thio-3-phenyl-pyridine is obtained.

When other mercaptides are used such as the sodium salts of the following products; benzylmercaptan, o-nitrobenzylmercaptan, m -nitrobenzylmercaptan, o-methylbenzylmeroaptan, m-methylbenzylmeroaptan, £ -methylbenzylmercaptan, 2,4-dimethyibenzylmercaptan, 3,4-dimethylbenzylmercaptyl, chlorobenzylmercaptylchlorobenz, 4-dichlorobenzylmercaptan, 3,4-dichlorobenzylmercaptan, 2,4,5-trichlorobenzylmercaptan, 2-chloro-5-nitrobenzylmercaptan, 5-amino-2,4-dichlorobenzylmercaptan, p-bromobenzylmercaptan, o-bromobenzylmercaptan, o-aminobenzylmercaptan, 3-amino-4methoxybenzylmercaptan, o-methylaminobenzylmercaptan, p-methoxybenzyl mereaptan, 4-methoxy-3-nitrobenzylmercaptan, 3,4-dimethoxÿbenzylmercaptan, 3,4-methyleneduanimethylbaptylbenzylmercaptan the corresponding 2-sulfide. Example 15 A mixture of 0.01 mole of 1- (2-cyanomethyl) -3-phenyl-225 Z ~ 1H_7-pyridone, 50 ml of acetic acid and 50 ml of sulfuric acid at 10 i is heated at reflux for 4 hours. The reaction mixture is then concentrated, poured into water and extracted thoroughly with chloroform. The combined chloroform extracts are dried over sodium sulfate and concentrated to give 1- (2-carboxyethyl) -330 phenyl-2- /^-1H_7-pyridone.

Example 16 A mixture of 0.01 mole of 1- (2-hydroxyethyl) -3-phenyl-2 ^ ~ 1H_7-pyridone and 25 ml of concentrated hydrochloric acid is heated in a sealed tube for 60 hours at 120 ° C. The reaction mixture is cooled, then concentrated in vacuo to give 1- (2-chloroethyl) 3-phenyl-2 - / “1H_7-pyridone.

The following examples illustrate the interconversion or the introduction of functional groups after the preparation of the phenylpyridone nucleus.

Example 17 - 5-ohloro-3-phenyl-2- / ~ 1H_7-pyridone 3-phenyl-2 - / “1H_7-pyridone (3.08 g) and N-chlorosuccinimide (2.7 g) are heated at reflux in methylene chloride (25 ml) for 28 hours under a nitrogen atmosphere. Dissolution occurs gradually. After cooling, the mixture is filtered to remove the succinimide, the filtrate is diluted with about 20 ml of methylene chloride, washed with water (twice about 50 ml), dried over magnesium sulfate, filtered, concentrated to give 3.2 g of a brown solid. By recrystallization from benzene (concentration to about 40 ml while hot), 815 mg of very pale pink cottony crystals are obtained, melting at 157.5-159 ° C. of 5-ohloro3-phenyl-2- / “1H_7-pyridone.

Example 18 - 5-dimé thylaTnino-3-phenyl-2 - / '~ 1 Hj7-Pvridone Of 5-ehloro-3-phenyl-2- /^-ÎH__&gt;7-pyridone (1 g) in anhydrous dimethylformamide (50 ml) is saturated with dimethylamine and the resulting mixture is heated in a stainless steel bomb for several hours. The solvent is removed under vacuum. The residue is distributed between chloroform and water, the chloroform layer is dried, the solvent is removed and the residue is chromatographed on a column of silica gel using a methanol-methylene chloride mixture (v / v as eluent) 0 - 100% MeOH) to obtain the product under the heading.

Example 19 - 3-P-hydroxyphenyl-2- / ~ 1 Hj7-T&gt; yridone 3 -p-methoxyphenyl-2- / ~ 1H_7-pyridone (2g) is added to 10 g of pyridine hydrochloride stirred at 188 ° 0. An atmosphere of dry nitrogen is maintained. The mixture is left to stand for 20 minutes, cooled and added to 45 g of ice. The crude product is collected, dried and recrystallized to give the product under heading.

The same, when the o- and m-methoxyphenyl-pyridones are used instead of the para isomer in the above reaction, the analogs o- and m-hydroxy are obtained.

Example 20 - 3- (p-aminophenyl) -2- / ~ 1H 7-pyridone 3- (p-aminophenyl) -2- / 1H_7-pyridone (1 g) in hot dioxane (50 ml) is reduced under hydrogen atmosphere in the presence of 0.3 g of 5% Pd / O. The mixture is filtered, the cake washed thoroughly with hot dioxane, the combined filtrates are concentrated in a residue which is recrystallized to obtain the product under heading.

Alternatively, when the dioxane solution is treated with a solution of hydrochloric acid in anhydrous ether, the hydrochloride precipitates. When the corresponding o- and m-nitrophenyl-pyridones are used in the reduction above, the o and m-aminophenyl-pyridones are obtained.

Example 21 - 3- (p-dimethylaminophenyl) -2- / ~ 1H 7-pyridone 3 - (] 3-nitrophenyl) -2- / 1H_7-pyridone (1 g) in methanol (100 ml) containing 1 glacial acetic acid (1 ml) and 37% formaldehyde solution (3 ml) is reduced in the presence of Raney nickel (1/4 tsp) under a hydrogen atmosphere. The mixture is filtered, the cake, washed with methanol and the combined filtrates are concentrated to a residue. Chromatography on an alumina column using a methanol / methylene chloride system (v / v 0-100%) as eluent gives the product under heading.

When the o- and m-nitro isomers are used in the above reduction instead of the para isomer, the corresponding o- and m-dimethylaminophenyl-2-pyridones are obtained.

Example 22 - 3- (p-oarhamidophenvl) -2- / ~ 1H_7-pyridones 3- (p-cyanophenyl) -2 - / ”1H_7-pyridone (5g) is added to 20 g of stirred concentrated sulfuric acid and cooled to ice temperature. the mixture is stirred overnight and is introduced into ice water; the crude product is collected, dried and recrystallized to give the product under heading. When the o and m-cyanophenyl-pyridones are used in the above reaction, the corresponding o- and m-carhamidophenyl isomers are obtained.

Example 23 - 3- (p-oarboxyphenyl) -2- / ~ 1H_7-nvrldone 3- (p-cyanophenyl) -2- / ~ 1H__&gt;7-pyridone (1 g) in 30 ml of a 1: 1 mixture of glacial acetic acid and 20% hydrochloric acid is heated for 12 hours, the solvent is removed under vacuum, the residue divided between chloroform and an almost saturated solution of sodium bicarbonate, the bicarbonate solution is filtered and acidified, the precipitate collected, dried and recrystallized to give the product under heading.

When the o- and m-cyanophenyl-pyridones are used in the above reaction, the corresponding o- and m-earboxyphenyl isomers are obtained.

EXAMPLE 24 1-methyl-5-phenyl-2- / ~ 15 7-Pvrldone sulfonic acid When 1-methyl-3-phenyl-2- / ~ 1H_7-pyridone is treated with chlorosulfonic acid according to the mode operative of German patent 601,896, 1-methyl-3-phenyl-2- / ~ 1H_7pyridone-5-sulfonic acid is obtained.

Example 25 - 3-phenyl-5-triphenylmethyl-2- / ~ 1 H_7-P.vrldone 3-phenyl-2- / ~ 1H_7-pyridone (3g) and trityl chloride (3 g) are intimately mixed and heated to about 250 ° C in a metal bath for 30 minutes; the reaction mixture is cooled and added with 60 ml of boiling ethanol; the solid is filtered, washed with fresh ethanol and renr-iata. 11 to give the product under heading.

EXAMPLE 26 5-amino-3-phenyl-2- / ~ 1H 7-pyridone When 5-nitro-3-phenyl-2- / ~ 1H 7-pyridone is reduced under the same conditions as in Example 20 above, the product is obtained under the heading.

When the 4- and 6-nitro isomers are used instead of the 5-nitro compound, the corresponding 4- and 6-amino-3-phenyl-2- / ~ 1H_7pyridones are obtained.

Example 27 - 5-dimethylaminomethyl-3-phenyl-2- / ~ 1H 7-pyridone 5-methyl-3-pbenyl-2- / ~ 1H 7-pyridone (0.01 m.) And N-bromosucciaimide ( 0.01 m.) In carbon tetrachloride (250 ml) are heated to reflux under irradiation for about 15 minutes (if necessary a trace of benzoyl peroxide is necessary to start the reaction), cooled and filtered, and the the filtrate is concentrated under vacuum to a residue.

The residue is taken up in dimethylformamide; dimethylamine is added, the container is sealed and heated, the solvent is removed under vacuum and the residue is chromatographed on an alumina column using as eluent the methylene methauolchloride system (v / v 0-100 ¢) to give the product under heading,

- Similarly, when the corresponding 4- and 6-methyl isomers are used, the corresponding 4- and 6-dimethylaminomethyl isomers are obtained.

Example 28 - 3- (p-mercaptophenyl) -2- / ~ 1H_7-pyridone This product is prepared from 3- (p-amino-phenyl) -2 / ”1 H_7-pyridone by the method of Tarbell &amp; Eukushima ( Org. Syn., '

Coll. Flight. III, p. 809), but using chloroform as the organic extraction liquid, omitting washing with 10% sodium hydroxide and hydrolyzing the intermediate thiocarbonate under milder conditions. The mixture is then acidified, the solvent removed under vacuum and the residue re-recrystallized, using aerated solvents to avoid the formation of disulfide.

When the o- and m-aminophenyl isomers are used instead of the para isomer in the above reaction, the corresponding σ- and m-mercapto isomers are obtained.

Example 29 Acid p- (2- / ~ 1 Hj7-ovridon-5-yl) b enzenesulfonic Qn employs the method used by Wallace / Tetrahydron Letters (1963) 1131_7 for benzenesulfonic acid.

3- (p-mercaptophenyl) -2- / 1H_7-pyridone is stirred at room temperature in dimethylformamide containing potassium hydroxide (1.3 M) under partial pressure of oxygen (1 atm.) for 24 hours. The mixture is acidified, the solvent removed under vacuum and the residue recrystallized to give the product under heading.

Likewise, when the o- and m-mercaptophenyl isomers are used in the above process, the corresponding o- and m-sulfonic aids are obtained.

Example 30 - p- (2- / ~ 1H_7-Pvridon-5-yl) benzenesulfonamide Aid p- (2 - / “1H_7-pyridon-3-yl) benzenesulfonic acid (0.005 m.) Is added to chloride chloride thionyle (50 ml) containing a drop of dimethylformamide. The mixture is stirred overnight at room temperature, the excess of thionyl chloride is ohassed under vacuum and the residue is subjected to a vacuum to remove all traces of thionyl chloride. the acid chloride is then taken up in anhydrous ether and added to an aqueous solution containing two equivalents of ammonia, subjected to stirring for several hours; the product is collected, dried and treated as in Example 4B above to hydrolyze the 2-chloro derivative possibly present. Recrystallization gives the product under heading.

When, in the above reaction, the isomeric o- and m-sulfonic acids are used, the corresponding o- and m-sulfonamides are obtained ·

When methylamine, dimethylamine or aniline is used instead of ammonia in the above reaction, the corresponding N-substituted sulfonamides are obtained.

Example 31 - 2-aoetoxy-5-phenyl-pyridine A mixture of 0.01 mole of 3-phenyl-pyridine-N-oxide is heated at reflux for 12 hours in 50 ml of acetic anhydride.

By concentration of the reaction mixture in a vacuum, the product is obtained under the heading.

Example 32 - 1-benzamido-3-phenvl-2- / ~ 1H_7-pyridone A. To a mixture of 0.01 mole of 1-amino-3-phenyl-2- /^_1H_7pyridone and 5.0 g of anhydrous potassium carbonate in 100 ml of chloroform, 0.01 mole of benzoyl chloride is added in portions with stirring. the reaction mixture is stirred for 4 hours at reflux, then cooled and filtered, the filtrate is concentrated in vacuo and gives the product under heading.

B. When acetyl chloride is used instead of benzoyl chloride in the example above, 1-acetamido3-phenyl-2- ^ 1H_7 ~ pyridone is obtained.

C. When carbobenzoxy chloride is used instead of benzoyl chloride in the example above (A), the

1-carbobenzoxyamino-3-phenyl-2 - / “1H_7-pyridone.

D. When ethyl chloroformate is used instead of benzoyl chloride in A above, 1-carbethoxyamino-3-phenyl-2- / “1H_7-pyridone is obtained.

E. A mixture of 0.01 mole of 1-amino-3-phenyl-2 - / “1H_7 ~ pyridone and 0.01 mole of benzaldehyde is heated at reflux for 3 hours in 30 ml of ethanol, the reaction mixture is then concentrated and gives 1-benzylidineamino-3 ~ phenyl-2- ^ ~ 1H_7-pyridone.

P. 0.01 mole of 1-amino-3-phenyl-2 - ^ “1H_&lt;_7-pyridone in 100 ml of anhydrous ether, 0.01 mol of phenylisocyanate is added. the reaction mixture is heated at reflux for one hour, then concentrated to give 1- (N'-phenyl-ureido) -3-phenyl-2-flHjpyridone.

Example 33 - 3- (n-methylsulfinylphenyl) -2- / ~ 1 Hj7-pyridone 3- (p-methylmercapbOphenyl) -2- /^-1H_7-pyridone (0.001 mole) is stirred in methanol (50 ml) and sodium metaperioate (0.001 mole) dissolved in the minimum amount of water is added.

The mixture is stirred at room temperature for several days and then filtered, the filtrate is concentrated in vacuo and distributed between chloroform and water. the chloroform layer is dried over sodium sulfate and the chloroform is removed in vacuo. The residue is recrystallized and gives the product under heading.

When the o- and m-methylmereaptophenyl-pyridones are used in the above process, the corresponding o- and m-methylsulfinylphenyl-pyridones are obtained.

Example 34 - 3- (p-methylsulfonylphenyl) -2- / ~ 1 H_7-pyridone Al g of 3- (p-methylmercaptophenyl) ~ 2-7^-1H_7-pyridone in glacial acetic acid (25 ml) hydrogen peroxide is added to 30 μl (2 ml) and the resulting mixture is stirred for several days at room temperature. Sodium bisulfite is added in an amount just necessary to destroy the excess peroxide. The solvent is removed in vacuo and the residue is recrystallized to give the above product.

When the £ - and mmethylmercaptophenyl-pyridones are used in the above process, the o- and m-methylsulfunylphenyl-2- /^-1H_7-corresponding pyridones.

Example 35 L_es test methods used are essentially those of 1) Winter and eoll. Proc. Soc. Exper. Biol. 111 (1962) p. 544 (inflammation of the foot caused by Carrogeenin); 2) Stark and eoll. Am. J. Pathol. 30 (1954), p. 616 (Arthritis adjuvant I); and 3) Newbould, Brit. J. Pharmacal. 24 (1965), p. 632 (Arthritis adjuvant II).

For example :

Compound (Dose in mg / kg body weight) Carrogeenin Adj. Arthr. I

-'T Dose Inhibition Dose Inhibition

WO

Dose

Arthr. II

Inhibition

3- phenyl-2- /^—1H_7 pyridone “

4- phenyl-2- / “1 H_7 pyridone“ = 38

100 = 54,7

12,5= 51,3

12,5 = 55

12,5 = 56,9